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61. 发明申请

US20030108862A1 Direct binding assay for identifying inhibitors of HCV polymerase 有权
标题翻译：用于鉴定HCV聚合酶抑制剂的直接结合测定
公开(公告)号：US20030108862A1
公开(公告)日：2003-06-12
申请号：US10211455
申请日：2002-08-02
申请人： Boehringer Ingelheim (Canada) Ltd.
发明人： George Kukolj , Pierre Louis Beaulieu , Ginette McKercher
IPC分类号： C12Q001/70 , A61K031/53 , A61K031/519 , A61K031/52
CPC分类号： G01N33/542 , C12Q1/48 , G01N2333/18 , G01N2333/91245 , G01N2500/02 , G01N2500/04
摘要： A method for identifying compounds binding to HCV polymerase comprising the steps of:contacting said HCV polymerase or an analog thereof with a probe formula I: 1 wherein A is O, S, N, NR1, or CR1, wherein R1 is defined herein; - - - represents either a single or a double bond; R2 is selected from: H, halogen, R21 , OR21 , SR21 , COOR21 , SO2N(R22)2, N(R22)2, CON(R22)2, NR22C(O)R22 or NR22C(O)NR22 wherein R21 and each R22 is defined herein; B is NR3 or CR3, wherein R3 is defined herein; with the proviso that, when A is not N, then one of A or B is either CR1 or CR3, K is N or CR4, wherein R4 is defined herein; L is N or CR5, wherein R5 has the same definition as R4 defined above; M is N or CR7, wherein R7 has the same definition as R4 defined above; R5 is C(Y1)Z wherein Y1 is O or S; and Z is N(R6a)R6 or OR6, wherein R6a is H or alkyl or NR61R62 wherein R61 and R62 are defined herein; and R6 is H, alkyl, cycloalkyl, alkenyl, Het, alkyl-aryl, alkyl-Het; or R6 is 2 wherein R7 and R8 and Q are as defined herein; Y2 is O or S; R9 is H, (C1-6 alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl, aryl, Het, (C1-6)alkyl-aryl or (C1-6)alkyl-Het, all of which optionally substituted with R90; or R9 is covalently bonded to either of R7 or R8 to form a 5- or 6-membered heterocycle; or a salt thereof; where the probe comprises a detectable label attached to any suitable position, whereby said probe binds to an HCV polymerase or an analog thereof and is capable of being displaced by an inhibitor thereof.
摘要翻译：用于鉴定与HCV聚合酶结合的化合物的方法，包括以下步骤：使所述HCV聚合酶或其类似物与式I的探针接触：其中A是O，S，N，NR1或CR1，其中R 1在本文中定义; - - - 表示单键或双键; R 2选自：H，卤素，R 21，OR 21，SR 21，COOR 21，SO 2 N（R 22）2，N（R 22）2，CON（R 22）2，NR 22 C（O）R 22或NR 22 C R22在本文中定义; B是NR 3或CR 3，其中R 3在本文中定义; 条件是当A不是N时，A或B中的一个是CR 1或CR 3，K是N或CR 4，其中R 4在本文中定义; L是N或CR5，其中R5具有与上述定义的R4相同的定义; M是N或CR 7，其中R7与上述定义的定义相同; R5是C（Y1）Z，其中Y1是O或S; 并且Z是N（R6a）R6或OR6，其中R6a是H或烷基或NR61R62，其中R61和R62在本文中定义; 且R 6为H，烷基，环烷基，烯基，Het，烷基 - 芳基，烷基-Het; 或R6是其中R7和R8和Q如本文所定义; Y2为O或S; R9是H，（C1-6烷基），（C3-7）环烷基或（C1-6）烷基 - （C3-7）环烷基，芳基，Het，（C1-6）烷基 - 芳基或（C1-6）烷基-Het，它们全部被R90取代; 或R

62. 发明申请

US20030087379A1 Assay for identifying inhibitors of HIV RT dimerization 有权
标题翻译：用于鉴定HIV RT二聚化抑制剂的测定
公开(公告)号：US20030087379A1
公开(公告)日：2003-05-08
申请号：US10205641
申请日：2002-07-25
申请人： Boehringer Ingelheim (Canada) Ltd.
发明人： Nicolas Sluis-Cremer , Michael Parniak , Alex Pelletier
IPC分类号： C12Q001/68 , C12P021/06 , C12P019/34 , C07K002/00 , C07K004/00 , C07K005/00 , C07K007/00 , C07K014/00 , C07K016/00 , C07K017/00 , A61K038/00
CPC分类号： C12Q1/48 , G01N2333/9125 , G01N2500/02
摘要： A method for measuring heterodimerization of HIV RT, which comprises the steps of: a) providing a first solution comprising p66 subunit homodimers in the presence of a dissociation agent; b) contacting the first solution with p51 RT subunits and incubating in the presence of a reassociation buffer to allow association of a complex of p66/p51 RT subunits, wherein one of the subunits comprises an affinity tag and the other of the subunits comprises a detectable label; c) contacting the incubate of step b) with an affinity medium under conditions that enable the p66/p51 complex to bind to the affinity medium; and d) determining the amount of complex formed by measuring the level of detectable label bound to the affinity medium (or by measuring the reconstituted RT polymerase activity). Steps a) to d) can be carried out in the presence or absence of a test compound followed by e) comparing the test compound sample to a control sample lacking the compound, whereby modulated p66/p51 complex formation in the test compound sample is indicative of the ability of the compound to modulate, inhibit or enhance heterodimerization. The method can be used to screen for inhibitors of HIV RT dimerization.
摘要翻译：一种用于测量HIV RT的异二聚化的方法，其包括以下步骤：a）在解离剂存在下提供包含p66亚基同源二聚体的第一溶液; b）使第一溶液与p51RT亚基接触，并在再结合缓冲液存在下孵育以允许p66 / p51 RT亚基的复合物缔合，其中一个亚基包含亲和标签，另一个亚基包含可检测的标签; c）使能使p66 / p51复合物与亲和介质结合的条件下使步骤b）的培养物与亲和介质接触; 和d）通过测量与亲和介质结合的可检测标记的水平（或通过测量重构的RT聚合酶活性）来确定形成的复合物的量。步骤a）至d）可以在存在或不存在测试化合物的情况下进行，随后e）将测试化合物样品与缺少化合物的对照样品进行比较，由此在测试化合物样品中调节的p66 / p51复合体形成是指示性的的化合物调节，抑制或增强异源二聚化的能力。该方法可用于筛选HIV RT二聚化抑制剂。

63. 发明申请

US20030082769A1 Human papillomavirus E2 transactivation domain/inhibitor co-crystal and x-ray coordinates defining the inhibitor binding pocket 有权
标题翻译：定义抑制剂结合口袋的人乳头瘤病毒E2反式激活结构域/抑制剂共晶体和x射线坐标
公开(公告)号：US20030082769A1
公开(公告)日：2003-05-01
申请号：US10193460
申请日：2002-07-11
申请人： Boehringer Ingelheim (Canada) Ltd.
发明人： Dale R. Cameron , Jacques Archambault , Christiane Yoakim , Peter White , Yong Wang
IPC分类号： G01N033/53 , G06F019/00 , G01N033/48 , G01N033/50 , C12N009/00
CPC分类号： C07D405/12 , C07D417/12 , C07K14/005 , C07K2299/00 , C12N2710/20022
摘要： A crystallizable composition, comprising an PV E2 TAD-like polypeptide of SEQ ID NO.2 complexed with an inhibitor L. The invention also provides a method for producing the crystallized HPV E2 TAD-inhibitor complex (HPV E2 TAD-L) comprising: a) mixing purified HPV E2 TAD, contained in a purfication buffer, with solublized inhibitor L to generate a complex solution containing the HPV E2 TAD-L complex; and b) crystallizing the complex from a) in a crystallization buffer. The invention also provides a method for producing crystallized apo HPV E2 TAD, comprising: a) mixing apo HPV E2 TAD, contained in a purification buffer, with a crystallization buffer. X-ray crystal structure coordinates the HPV E2 TAD-L complex, are also provided, which define an inhibitor binding pocket. The inhibitor binding pocket is useful for screening potential small molecule inhibitors that bind to the pocket.
摘要翻译：包含与抑制剂L复合的SEQ ID NO：2的PV E2 TAD样多肽的可结晶组合物。本发明还提供了一种生产结晶的HPV E2 TAD抑制剂复合物（HPV E2 TAD-L）的方法，包括：将纯化的含有缓冲液的HPV E2 TAD与溶出的抑制剂L混合以产生含有HPV E2 TAD-L复合物的复合溶液; 和b）从结晶缓冲液中的a）结晶复合物。本发明还提供了一种用于生产结晶apo HPV E2 TAD的方法，其包括：a）将包含在纯化缓冲液中的apo HPV E2 TAD与结晶缓冲液混合。还提供X射线晶体结构协调HPV E2 TAD-L复合物，其定义了抑制剂结合口袋。抑制剂结合口袋可用于筛选结合口袋的潜在小分子抑制剂。

64. 发明授权

US5830864A Antiherpes peptide derivatives having a ureido n-terminus 失效
标题翻译：具有脲基n末端的抗原肽衍生物
公开(公告)号：US5830864A
公开(公告)日：1998-11-03
申请号：US502981
申请日：1995-07-17
申请人： Robert Deziel , Neil Moss , Raymond Plante
发明人： Robert Deziel , Neil Moss , Raymond Plante
IPC分类号： A61K38/00 , C07K5/083 , C07K5/087 , C07K5/093 , C07K5/103 , C07K5/107 , A61K38/07 , C07K5/10
CPC分类号： C07K5/0819 , C07K5/0808 , C07K5/081 , C07K5/0812 , C07K5/101 , C07K5/1016 , A61K38/00
摘要： Disclosed herein are peptide derivatives of the formula A--B--NHCH{CH.sub.2 C(O)R.sup.1 }C(O)--NHCH{CR.sup.2 (R.sup.3)COOH}C(O)--D wherein A is a terminal group, for example, an alkylaminocarbonyl or a phenylalkylaminocarbonyl; B is an amino acid residue; R.sup.1 is alkyl, cycloalkyl or a disubsubstituted amino; R.sup.2 is hydrogen or alkyl and R.sup.3 is alkyl, or R.sup.2 is hydrogen and R.sup.3 is phenylakyl, or R.sup.2 and R.sup.3 are joined to form a cycloalkyl; and D is a terminal unit, for example, an alkylamino or a monovalent amino acid radical such as NHCH(alkyl)C(O)OH. The derivatives are useful in treating herpes infections.
摘要翻译：本文公开了式A-B-NHCH（CH 2 C（O）R 1）C（O）-NHCH（CR 2（R 3）COOH）C（O） - ）的肽衍生物，其中A是末端基团，例如烷基氨基羰基或苯基烷基氨基羰基; B是氨基酸残基; R1是烷基，环烷基或二取代的氨基; R2是氢或烷基，R3是烷基，或R2是氢，R3是苯基烷基，或R2和R3连接形成环烷基; 并且D是末端单元，例如烷基氨基或单价氨基酸基团，例如NHCH（烷基）C（O）OH。该衍生物可用于治疗疱疹感染。

65. 发明授权

US5808085A Stereoselective preparation of 2-substituted succinic acid derivatives 失效
标题翻译： 2-取代琥珀酸衍生物的立体选择性制备
公开(公告)号：US5808085A
公开(公告)日：1998-09-15
申请号：US767917
申请日：1996-12-17
申请人： Murray Douglas Bailey
发明人： Murray Douglas Bailey
IPC分类号： C12P41/00 , C07C19/01 , C07C19/075 , C07C69/65 , C07C233/09 , C07C235/76 , C07D213/40 , C07D213/56 , C07D213/75 , C07D277/20 , C07D277/38 , C07D277/40 , C07D277/48 , C07D401/12 , C07D405/12 , C07D409/12 , C07D413/12 , C07D417/12
CPC分类号： C07B57/00 , C07C69/65 , C07D213/38 , C07D277/40 , C12P13/02 , C12P41/005 , C12P7/40 , C12P7/62 , C07B2200/07
摘要： A highly efficient and practical means has been developed which enables compounds of the formula: ##STR1## wherein R.sup.1 is lower alkoxy, lower alkylamino, di-(loweralkyl) amino, or the monovalent radical A--NR.sup.3, wherein A is lower alkyl or A is R.sup.4 R.sup.5 NC(O)CH.sub.2 wherein, for example, R.sup.4 is hydrogen or alkyl and R.sup.5 is hydrogen, alkyl or a substituted alkyl, or R.sup.5 is R.sup.6 R.sup.7 N-Alk wherein R.sup.6 and R.sup.7 each is hydrogen or lower alkyl and Alk is a divalent alkyl radical; R.sup.3 is, for example, benzyl, alkyl or a substituted alkyl; and R.sup.2 is, inter alia, alkyl, cycloalkyl, 1H-imidazol-4-yl, 4-thiazolyl or 2-amino-4-thiazolyl; to be prepared through the kinetic resolution of a compound of the formula: ##STR2## wherein R.sup.1 is as defined herein, R.sup.2 is as defined herein, and B is lower alkyl. These compounds are useful intermediates in the synthesis of renin inhibiting compounds.
摘要翻译：已经开发了一种高效实用的手段，其使得下式的化合物：其中R 1是低级烷氧基，低级烷基氨基，二 - （低级烷基）氨基或一价基团A-NR 3，其中A是低级烷基或A 是R4R5NC（O）CH2，其中例如R4是氢或烷基，R5是氢，烷基或取代的烷基，或R5是R6R7N-Alk，其中R6和R7各自是氢或低级烷基，Alk是二价烷基 ; R3是例如苄基，烷基或取代的烷基; R 2尤其是烷基，环烷基，1H-咪唑-4-基，4-噻唑基或2-氨基-4-噻唑基; 通过下式化合物的动力学拆分制备：其中R 1如本文所定义，R 2如本文所定义，B是低级烷基。这些化合物是合成肾素抑制化合物的有用中间体。

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